1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to substituted nicotinamides and analogs, and the discovery that these compounds are activators of caspases and inducers of apoptosis. The invention also relates to the use of these compounds as therapeutically effective anti-cancer agents.
2. Description of Background Art
Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-437 (1965); Ellis, et al., Dev. 112:591-603 (1991); Vaux, et al., Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721).
There are a number of morphological changes shared by cells experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).
Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A. H., in Cell Death in Biology and Pathology, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34). A cell activates its internally encoded suicide program as a result of either internal or external signals. The suicide program is executed through the activation of a carefully regulated genetic program (Wyllie, et al., Int. Rev. Cyt. 68:251 (1980); Ellis, et al., Ann. Rev. Cell Bio. 7:663 (1991)). Apoptotic cells and bodies are usually recognized and cleared by neighboring cells or macrophages before lysis. Because of this clearance mechanism, inflammation is not induced despite the clearance of great numbers of cells (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).
It has been found that a group of proteases are a key element in apoptosis (see, e.g., Thomberry, Chemistry and Biology 5:R97-R103 (1998); Thomberry, British Med. Bull. 53:478-490 (1996)). Genetic studies in the nematode Caenorhabditis elegans revealed that apoptotic cell death involves at least 14 genes, two of which are the pro-apoptotic (death-promoting) ced (for cell death abnonnal) genes, ced-3 and ced-4. CED-3 is homologous to interleukin 1 beta-converting enzyme, a cysteine protease, which is now called caspase-1. When these data were ultimately applied to mammals, and upon further extensive investigation, it was found that the mammalian apoptosis system appears to involve a cascade of caspases, or a system that behaves like a cascade of caspases. At present, the caspase family of cysteine proteases comprises 14 different members, and more may be discovered in the future. All known caspases are synthesized as zymogens that require cleavage at an aspartyl residue prior to forming the active enzyme. Thus, caspases are capable of activating other caspases, in the manner of an amplifying cascade.
Apoptosis and caspases are thought to be crucial in the development of cancer (Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Humana Press (1999)). There is mounting evidence that cancer cells, while containing caspases, lack parts of the molecular machinery that activates the caspase cascade. This makes the cancer cells lose their capacity to undergo cellular suicide and the cells become cancerous. In the case of the apoptosis process, control points are known to exist that represent points for intervention leading to activation. These control points include the CED-9-BCL-like and CED-3-ICE-like gene family products, which are intrinsic proteins regulating the decision of a cell to survive or die and executing part of the cell death process itself, respectively (see, Schmitt, et al., Biochem. CelL Biol. 75:301-314 (1997)). BCL-like proteins include BCL-xL and BAX-alpha, which appear to function upstream of caspase activation. BCL-xL appears to prevent activation of the apoptotic protease cascade, whereas BAX-alpha accelerates activation of the apoptotic protease cascade.
It has been shown that chemotherapeutic (anti-cancer) drugs can trigger cancer cells to undergo suicide by activating the dormant caspase cascade. This may be a crucial aspect of the mode of action of most, if not all, known anticancer drugs (Los, et al., Blood 90:3118-3129 (1997); Friesen, et al., Nat. Med. 2:574 (1996)). The mechanism of action of current antineoplastic drugs frequently involves an attack at specific phases of the cell cycle. In brief, the cell cycle refers to the stages through which cells normally progress during their lifetimes. Normally, cells exist in a resting phase termed Go. During multiplication, cells progress to a stage in which DNA synthesis occurs, termed S. Later, cell division, or mitosis occurs, in a phase called M. Antineoplastic drugs such as cytosine arabinoside, hydroxyurea, 6-mercaptopurine, and methotrexate are S phase specific, whereas antineoplastic drugs such as vincristine, vinblastine, and paclitaxel are M phase specific. Many slow growing tumors, for example colon cancers, exist primarily in the Go phase, whereas rapidly proliferating normal tissues, for example bone marrow, exist primarily in the S or M phase. Thus, a drug like 6-mercaptopurine can cause bone marrow toxicity while remaining ineffective for a slow growing tumor. Further aspects of the chemotherapy of neoplastic diseases are known to those skilled in the art (See, e.g., Hardman, et al., eds., Goodman and Gilman""s The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York (1996), pp. 1225-1287). Thus, it is clear that the possibility exists for the activation of the caspase cascade, although the exact mechanisms for doing so are not clear at this point. It is equally clear that insufficient activity of the caspase cascade and consequent apoptotic events are implicated in various types of cancer. The development of caspase cascade activators and inducers of apoptosis is a highly desirable goal in the development of therapeutically effective antineoplastic agents. Moreover, since autoimmune disease and certain degenerative diseases also involve the proliferation of abnormal cells, therapeutic treatment for these diseases could also involve the enhancement of the apoptotic process through the administration of appropriate caspase cascade activators and inducers of apoptosis.
PCT published patent application WO95/25723 discloses anilide derivatives as fungicides: 
wherein,
X is O or S;
A is a 6 membered heteroaryl group comprising at least one nitrogen atom, which is optionally substituted by one or more of the group R2;
R1 is alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, or amino, (each of which is optionally substituted), Yxe2x80x2xe2x80x94Xxe2x80x94, halogen, cyano, nitro, acyl, acyloxy, optionally substituted heterocyclyl or optionally substituted phenyl; or two adjacent groups together with the carbon atoms to which they are attached can form an optionally substituted benzo ring;
R2 is the same meaning as R1 or two adjacent groups together with the carbon atoms to which they are attached can form an optionally substituted heterocyclic ring;
Y is alkyl, cycloalkyl, cycloalkenyl, alkenyl or alkynyl, each of which is optionally substituted, hydrogen or acyl;
Y1 has the same meaning as Y or is optionally substituted phenyl or optionally substituted heterocyclyl;
Z is C(xe2x95x90X)xe2x80x94X2xe2x80x94R3, cyano, nitro, amino, acyl, optionally substituted heterocyclyl, xe2x80x94C(R5)xe2x95x90Nxe2x80x94OR6 or xe2x80x94C(R5)xe2x95x90Nxe2x80x94NR6R7;
R3 is alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, phenyl or heterocyclyl, each of which is optionally substituted, hydrogen or an inorganic or organic cationic group;
X and X2, which may be the same or different, are O or S;
R5, R6 and R7, which may be the same or different, are alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, phenyl or heterocyclyl, each of which is optionally substituted or hydrogen or R6 and R7 together with the atom(s) to which they are attached can form a ring;
and n is 0 to 4,
together with complexes with metal salts, as well as salts with bases of compounds which are acids and salts with acids of compounds which are bases, with the proviso that when Y is hydrogen and
i) when Z is carboxy, methoxycarbonyl or ethoxycarbonyl ring A is not unsubstututed pyridyl or pyrazinyl; and
ii) when Z is carboxy and n is 0, A is not 2-chloro-3-pyridyl, 6-(2-diethylaminoethoxy)-3-pyridyl or a 2-pyridyl group.
PCT WO9936391 discloses benzenesulfonamide, benzamide, diarylsulfone and benzophenone compounds as pharmacological agents in the treatment of cancer, psoriasis, vascular restenosis, infections, atherosclerosis and hypercholesterolemia: 
wherein, A represents N or Cxe2x80x94R1, B represents N or Cxe2x80x94R5; and
R1 and R5 independently represent hydrogen, halogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, xe2x80x94OR6, xe2x80x94NR6R7, xe2x80x94S(O)mR6, xe2x80x94CN, xe2x80x94NO2, xe2x80x94S(O)nNR6R7 or xe2x80x94N3; wherein R6 and R7 are independently selected from hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl;
m is an integer of from 0 to 3;
n is an integer of from 1 to 2;
R2 and R3 are independently xe2x80x94OR8, xe2x80x94SR8, and xe2x80x94NR8R9, wherein R8 and R9 are independently hydrogen, (C1-C6)alkyl, (C1-C6)heteroalkyl;
R4 is hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, xe2x80x94OR10, xe2x80x94SR10, or xe2x80x94NR10R11; wherein R10 and R11 are independently hydrogen, (C1-C6)alkyl, (C1-C6)heteroalkyl;
optionally, R1 is linked to R2 to form a fused ring, R2 is linked to R3 to form a fused ring, or R2 is linked to both R1 and R3 to form two additional fused rings;
X represents xe2x80x94S(O)p or xe2x80x94C(O)xe2x80x94, wherein p is 1 or 2;
Y represents a single bond, xe2x80x94CH2xe2x80x94 or xe2x80x94N(R12)xe2x80x94, wherein R12 is selected from hydrogen, (C1-C6)alkyl, (C1-C6)heteroalkyl and arylalkyl; and
Z represents an aryl group or an arylalkyl group.
The present invention is related to the discovery that substituted nicotinamides and nicotinamide analogs as represented in Formula V are activators of the caspase cascade and inducers of apoptosis: 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Arxe2x80x2 and Ar are independently optionally substituted aryl or optionally substituted heteroaryl, provided that the ring structure of said optionally substituted heteroaryl comprises not more than two nitrogen atoms; and
R11 is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted.
Thus, an aspect of the present invention is directed to the use of compounds of Formula V as inducers of apoptosis.
A second aspect of the present invention is to provide a method for treating, preventing or ameliorating neoplasia and cancer by administering a compound of Formula V to a mammal in need of such treatment.
Many of the compounds within the scope of the present invention are novel compounds. Therefore, a third aspect of the present invention is to provide novel compounds of Formula V, and to also provide for the use of these novel compounds for treating, preventing or ameliorating neoplasia and cancer.
A fourth aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the induction of apoptosis, containing an effective amount of a compound of Formula V in admixture with one or more pharmaceutically acceptable carriers or diluents.
A fifth aspect of the present invention is directed to methods for the preparation of novel compounds of Formula V.